Hepatitis B virus (HBV), a small double stranded DNA virus, can cause a wide spectrum of clinical presentations: asymptomatic carrier state, acute self-limited hepatitis, fulminant hepatitis, and chronic liver diseases including chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. It has a circular genome of 3182 to 3221 base pairs (bp). Four major subtypes have been identified and can be differentiated by antibodies that recognize the different epitopes on the HBV surface. The HBsAg particles carry the common determinant, “a”, as well as d or y and w or r subtype determinants, and are classified into the four major subtypes, i.e., adw, adr, ayw and ayr. Rare sera contain HBsAg particles with all four-subtype determinants (adywr). The antigenic determinants for the main HBV subtypes: adw, adr, ayw and ayr lie in the surface or “S” polypeptide. Two amino acid residues in particular, encoded by the S gene at codon positions 122 and 160, have been postulated to determine the different antigenic subtypes. While, the preC regions have frequently been reported to have mutations rendering HBe Ag negative. The virus has a high rate of mutation relative to other DNA viruses due to its mode of replication by reverse transcriptase of its pregenomic RNA. The importance of a novel mutant can be reflected in vaccine escape and HBsAg detection failure, implicating a public health problem.